Neonatal encephalopathy (NE) due to hypoxia-ischemia is a major public health concern as it occurs in 6/1000 live term births and has devastating consequences. Many affected neonates suffer lifelong motor disabilities and epilepsy, but increasingly the high prevalence of cognitive and behavioral disabilities is becoming appreciated. In hypoxia-ischemia there is a decrease in blood and oxygen delivery, followed by reperfusion with transient energy recovery. What follows is a window of opportunity where excitotoxicity and associated increased cerebral metabolism eventually lead to secondary energy failure and irreversible cell death. In this window, therapeutic hypothermia (TH) is currently the only treatment available with proven efficacy. TH acts primarily by decreasing cerebral metabolism, thus preserving energy stores. Although the current gold standard for brain injury detection is magnetic resonance imaging (MRI), MRI is impractical as a screening tool and cannot provide bedside monitoring to optimize individual responses to therapies. Commercially available continuous wave (CW) near infrared spectroscopy (NIRS) systems provide bedside measures of cerebral oxygen saturation (SO2) but SO2 alone cannot assess oxygen metabolism, as oxygen delivery is not taken into account. What is needed is a bedside tool that can monitor cerebral metabolism to detect elevations in metabolism that suggest evolving hypoxic-ischemic injury, and decreases in metabolism that suggest response to therapy. Cerebral oxygen consumption (CMRO2) is a direct measure of cerebral metabolism and therefore we propose to measure an index of CMRO2 at the bedside using the innovative combination of Frequency Domain Near-Infrared Spectroscopy (FDNIRS) and Diffuse Correlation Spectroscopy (DCS). Our initial studies show that CMRO2 is elevated in neonates with MRI evidence of perinatal brain injury, and confirm that neonates on TH have significantly lower CMRO2 than normal controls. Following these exciting results, and in response to the RFA PAR-10-230 Innovative Therapies and Tools for Screenable Disorders in Newborns we now propose a feasibility study to determine if FDNIRS-DCS can screen for involvement, assess response to treatment, and predict outcomes in one of the largest neonatal populations requiring early screening and immediate intervention: neonatal encephalopathy. To assess early outcomes we propose an innovative combination of advanced neurobehavioral testing, regional FDNIRS-DCS measures and quantitative MRI analysis using MRIs obtained without sedation. If our hypotheses prove true, we will be poised to determine if bedside indices of CMRO2 provided by FDNIRS-DCS can optimize TH for individual neonates, thereby improving neurodevelopmental outcomes. Success at this stage will also allow exploration of the potential for FDNIRS-DCS to determine the additional benefits of emerging new treatments for NE and to screen for other treatable neonatal disorders.